CN106349090A - Bisoprolol fumarate I crystal form and preparation method thereof - Google Patents
Bisoprolol fumarate I crystal form and preparation method thereof Download PDFInfo
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- CN106349090A CN106349090A CN201610604361.6A CN201610604361A CN106349090A CN 106349090 A CN106349090 A CN 106349090A CN 201610604361 A CN201610604361 A CN 201610604361A CN 106349090 A CN106349090 A CN 106349090A
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- bisoprolol fumarate
- crystal formation
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- bisoprolol
- fumarate
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- RZPZLFIUFMNCLY-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 RZPZLFIUFMNCLY-WLHGVMLRSA-N 0.000 title claims abstract description 62
- 229960005400 bisoprolol fumarate Drugs 0.000 title claims abstract description 62
- 239000013078 crystal Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 43
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 14
- 238000002386 leaching Methods 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000010583 slow cooling Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000009413 insulation Methods 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 229960002781 bisoprolol Drugs 0.000 claims description 3
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 238000004448 titration Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application refers to the field of a drug crystal form, and particularly relates to a bisoprolol fumarate I crystal form and a preparation method of the bisoprolol fumarate I crystal form. The bisoprolol fumarate I crystal form prepared by the method of the application is gentle in reaction condition, simple in operation, and good in reproducibility; the use of single recrystallizing method can significantly improve yield and quality of bisoprolol fumarate; the purity is high, the dissolving effect is good, and the crystal form quality is stable; thus the industrial production condition is controllable; the bisoprolol fumarate I crystal form is more suitable for large-scale production.
Description
Technical field
The application is related to drug crystal forms field and in particular to a kind of Bisoprolol Fumarate i crystal formation and preparation method thereof.
Background technology
Bisoprolol Fumarate (bisoprolol fumarate), chemical name 1- [4- [[2- (1- methyl ethoxy) ethoxy
Base] methyl] phenoxy group] -3- [(1- Methylethyl) amido] -2- propanoic acid fumarate, its structural formula is as follows:
Bisoprolol Fumarate is beta-blocker, has high-affinity to the β1-receptor of bronchus and vascular smooth muscle,
Thus distending the blood vessels, blood pressure reduces.It is clinically used for treating hypertension, coronary heart diseases and angina pectoris and chronic stable DHF
Deng disease.This medicine is German e.merk company and research and development in 1978, and be859425, us4258062 disclose its synthesis
The content of technique.Subsequently Japan medical science institute has carried out the research improving yield and reducing by-product to wherein one step etherification reaction.
Patent publication No. cn 1590366a is improved to the synthesis of Bisoprolol Fumarate, after through ethyl acetate
It is recrystallized to give Bisoprolol Fumarate.It is new that Patent publication No cn 103664657a describes a kind of Bisoprolol Fumarate
Synthesis technique, free state bisoprolol is dissolved in ethanol, reacts 2h, cooling crystallization with fumaric acid, filter, obtain rich horse at 50 DEG C
Sour bisoprolol.
At present, the existing patent of Bisoprolol Fumarate concentrates on synthesis technique or preparation research, is not directed to fumaric acid ratio
The relevant report of any crystal formation of Suo Luoer.
Drug crystal forms research is new drug development, controlling of production process and the indispensable important component part of formulation design.
The polymorphism of analysis medicine and its property, contribute to according to characteristics such as its bioavailability, stability in the research of medicine,
Select suitable crystal formation and preparation, it is to avoid because crystal formation problem leads to the invalid and possible potential safety hazard of medicine.Therefore, this area
There is still a need for for further study to the crystal formation of described compound, develop the crystal formation of new suitable needs, the application meets this
The demand of sample.
Content of the invention
The application by conducting in-depth research to Bisoprolol Fumarate, had been surprisingly found that a kind of dissolubility more preferably,
Stability more preferably, draws moist less Bisoprolol Fumarate novel crystal forms.
This application provides the i crystal formation of Bisoprolol Fumarate, carry out x-ray powder mensure, its figure using cu-ka ray
Compose and there is the angle of diffraction shown in following table, interplanar distance and relative intensity:
Wherein, the error of the 2 θ angles of diffraction is ± 0.2.
The dsc collection of illustrative plates of this crystal formation is shown in 103.63 DEG C absworption peak.Tga shows that this crystal form samples is heated to 236.99 DEG C
When thermal weight loss mass percent be 8.613%；Being heated to thermal weight loss mass percent when 297.03 DEG C is 36.17%；It is heated to
When 342.87 DEG C, thermal weight loss mass percent is 52.29%；Sample carryover amount is 2.664%.With kf method, water is carried out to this crystal formation
Point mensure show that its water content is 0.1%, is anhydrous crystal forms, is defined as Bisoprolol Fumarate i crystal formation.
Further, the x-ray powder that the application Bisoprolol Fumarate i crystal formation has substantially as shown in Figure 1 spreads out
Penetrate collection of illustrative plates.
Disclosed herein as well is the preparation method of Bisoprolol Fumarate i crystal formation, specifically comprise the following steps that
(1) Bisoprolol Fumarate is dissolved in isopropanol, the mass volume ratio of Bisoprolol Fumarate and isopropanol
For 1g:(2ml～5ml), 40 DEG C～60 DEG C of solution temperature；
(2) sucking filtration is carried out to step (1) resulting solution；
(3) under the stirring of 108r/min～136r/min rotating speed, by step (2) gained filtrate slow cooling to 10 DEG C～20
DEG C crystallize 3h～5h；
(4) step (3) gained solid is carried out sucking filtration；
(5) step (4) gained filter cake is vacuum dried at 40 DEG C～60 DEG C 4h～8h.
Wherein, in step (1) Bisoprolol Fumarate and isopropanol the preferred 1g:(3ml～4ml of mass volume ratio), molten
Preferably 45 DEG C～55 DEG C of temperature of solution.
Wherein, the preferred 120r/min～130r/min of institute's speed of agitator in step (3), recrystallization temperature preferably 10 DEG C～15
DEG C, crystallize time preferred 4h～4.5h.
Wherein, preferred 5h～6h drying time in step (5), preferably 45 DEG C～55 DEG C of described temperature conditionss.
Bisoprolol Fumarate i crystal formation using technical scheme preparation has the advantage that
1st, compared with Bisoprolol Fumarate crude product, it is lower that the novel crystal forms of the application have a relevant material, dissolubility more preferably,
Draw moist considerably lower, the more excellent advantage of product quality；Using the crystal formation of the application, when carrying out follow-up preparation research, only need
Common process condition and sealed storage is wanted can effectively to guarantee the matter in follow-up formulation products storing process and formulation process
Amount is stable.Overcome and draw moist too good general and can propose requirements at the higher level to follow-up formulation and technology, condition of storage, if desired for using moistureproof
Performance and lucifuge packaging of good performance etc., and overcome in production process because raw material moisture absorption is likely to result in unknown impuritie
The shortcomings of affect dissolution in increase or production process.
2nd, adopt the Bisoprolol Fumarate crystal formation of the application preparation, reaction condition is gentle, simple to operate, favorable reproducibility,
Using single recrystallization method, required quantity of solvent is little and is conducive to recycling, and can effectively reduce reagent cost, save energy
Source, is conducive to environmental protection.
3rd, by controlling to the key process parameter of the application preparation technology, can significantly improve Bisoprolol Fumarate and
Yield and quality, purity is high, and result of extraction is good, and crystal formation steady quality, so as to realize commercial production conditions controlled, is more suitable for big
Large-scale production.
Brief description
The xrpd collection of illustrative plates of Fig. 1 embodiment 1 Bisoprolol Fumarate crystal formation
The dsc collection of illustrative plates of Fig. 2 embodiment 1 Bisoprolol Fumarate crystal formation
The hplc collection of illustrative plates of Fig. 3 embodiment 1 Bisoprolol Fumarate crystal formation
Specific embodiment
Below with reference to embodiment, the application is described in further detail, embodiments herein is merely to illustrate this
The technical scheme of application, not limits the spirit and scope of the application.
The mensure of x-ray powder diffraction (xrpd) described herein is to be spread out using the great unit in Dandong dx-2700x powder
Penetrate instrument to be acquired, design parameter is as shown in the table:
Differential scanning calorimetric analysis (dsc) determination data described herein gathers in taq2000 differential scanning calorimeter,
Instrument parameter is as shown in the table:
| dsc | |
| Specimen disc | Aluminium dish, gland |
| Temperature range | - 300 DEG C of room temperature |
| Sweep speed | 10 DEG C/min |
| Protective gas | Nitrogen |
Herein described " room temperature " refers to that temperature is between 10～25 DEG C.
The application hplc is carried out using Agilent agilent1260dad type chromatograph of liquid.
The relevant substance-measuring of the application is carried out using following condition:
(1) chromatographic column: octadecylsilane chemically bonded silica is filler (20 DEG C of column temperature)；
(2) mobile phase a:10g/l phosphoric acid solution；；
The acetonitrile solution of mobile phase b:10g/l phosphoric acid；
The gradient of mobile phase a and b see table:
| Time (min) | Mobile phase a (%, v/v) | Mobile phase b (%, v/v) |
| 0-4 | 95 | 5 |
| 4-8 | 95→80 | 5→20 |
| 8-15 | 80 | 20 |
| 15-34 | 80→20 | 20→80 |
| 34-36 | 20 | 80 |
| 36-45 | 20-95 | 80-5 |
| 45-50 | 95 | 5 |
(3) detector: UV absorption photometer (wavelength: 225nm)；
(4) flow velocity: 1ml/min；
(6) need testing solution: precision weighs test sample 25mg, is dissolved with diluent and is diluted to 25.0ml, shakes up and obtains final product
(1mg/ml)；
Contrast solution: pipette 1.0ml need testing solution to 100ml measuring bottle, after diluted to scale, pipette this
Solution 2.0ml diluted, to 10.0ml, obtains final product (0.2%)；
(7) sample size: 10 μ l.
(8) computing formula:
In formula: aSampleImpurity peak area in need testing solution；aRightImpurity peak area in reference substance solution；
cRightImpurity concentration in reference substance solution, μ g/ml；cSampleNeed testing solution concentration, μ g/ml.
The application assay is carried out according to content detection condition in ep8.0 Bisoprolol Fumarate raw material.
1st, take Bisoprolol Fumarate 0.300g to be dissolved in the anhydrous glacial acetic acid of 50ml, according to potentiometric titration, use 0.1mol/
L perchloric acid titration drop surely to terminal, and the result blank correction by titration.Perchloric acid titration liquid (the 0.1mol/ of every 1ml
L) be equivalent to (c of 38.35mg18h31no4)2.c4h4o4.
2nd, computing formula:
Perchloric acid titration liquid converted score
In formula, c0Represent perchloric acid titration liquid in temperature t0When the concentration demarcated, mol/l；
t1Represent the temperature of perchloric acid titration drop timing；
In formula, c represents the concentration of perchloric acid titration liquid, mol/l；
V represents the volume number that test sample consumes perchloric acid titration liquid, ml；
wSampleRepresent the weighing of test sample, g；
P represents test sample loss on drying percentage rate, %；
X represents test sample and calculates by dry product, containing (c18h31no4)2·c4h4o4Percentage composition, %.
Embodiment 1: the preparation of Bisoprolol Fumarate i crystal formation
20g Bisoprolol Fumarate is dissolved in 60ml isopropanol, solution temperature is 55 DEG C；Negative pressure leaching；Filtrate exists
Under the stirring of 120r/min rotating speed, slow cooling to 15 DEG C～20 DEG C crystallize 4h；Negative pressure leaching；Gained filter cake is put in vacuum drying oven
55 DEG C of insulation is dried 5.5h, obtains white powdery solids 18.72g, and yield is 93.6%.This white powdery solids content is
The relevant material of 100.2%, hplc always miscellaneous 0.20%, maximum single miscellaneous 0.07%.
This sample dsc is shown in 103.63 DEG C absworption peak.Tga shows that this crystallized sample is heated to 236.99 DEG C of intermittent fever and loses
Weight mass percent is 8.613%；Being heated to thermal weight loss mass percent when 297.03 DEG C is 36.17%；It is heated to 342.87
DEG C when thermal weight loss mass percent be 52.29%；Sample carryover amount is 2.664%.With kf method, moisture is carried out to this crystallized sample
Mensure show that its water content is 0.1%.
Learnt according to result above, this crystal formation is anhydrous crystal forms, is defined as Bisoprolol Fumarate i crystal formation.Using cu-ka
Ray carries out x-ray powder mensure, and its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and a relative intensity:
Wherein, the error of the 2 θ angles of diffraction is ± 0.2.
Further, i crystal formation has x-ray powder diffraction spectrum substantially as shown in Figure 1.
Embodiment 2: the preparation of Bisoprolol Fumarate i crystal formation
50g Bisoprolol Fumarate is dissolved in 200ml isopropanol, solution temperature is 45 DEG C；Negative pressure leaching；Filtrate exists
The lower slow cooling of 108r/min rotating speed stirring is to 10 DEG C～15 DEG C crystallize 3h；Negative pressure leaching；Gained filter cake is put in vacuum drying oven
50 DEG C of insulation is dried 8h, obtains white powdery solids 46.6g, and yield is 93.2%.
This white powdery solids content is the relevant material of 100.1%, hplc always miscellaneous 0.22%, maximum single miscellaneous 0.06%.
Dsc test result is consistent with embodiment 1 data.Spread out diffracting spectrum and embodiment 1 of x-ray powder keeps one substantially
Cause.
Embodiment 3: the preparation of Bisoprolol Fumarate i crystal formation
1000g Bisoprolol Fumarate is dissolved in 3.2l isopropanol, solution temperature is 50 DEG C；Negative pressure leaching；Filtrate
Under the stirring of 136r/min rotating speed, slow cooling is to 10 DEG C～15 DEG C crystallize 3.5h；Negative pressure leaching；Gained filter cake is put into vacuum and is dried
In case, 60 DEG C of insulation is dried 6h, obtains white powdery solids 941g, and yield is 94.1%.
This white powdery solids content is the relevant material of 99.6%, hplc always miscellaneous 0.35%, maximum single miscellaneous 0.07%.
Dsc test result is consistent with embodiment 1 data.Spread out diffracting spectrum and embodiment 1 of x-ray powder keeps one substantially
Cause.
Embodiment 4: the preparation of Bisoprolol Fumarate i crystal formation
10g Bisoprolol Fumarate is dissolved in 50ml isopropanol, solution temperature is 40 DEG C；Negative pressure leaching；Filtrate exists
The lower slow cooling of 120r/min rotating speed stirring is to 14 DEG C～16 DEG C crystallize 5h；Negative pressure leaching；Gained filter cake is put in vacuum drying oven
45 DEG C of insulation is dried 5h, obtains white powdery solids 9.25g, and yield is 92.5%.
This white powdery solids content is the relevant material of 100.1%, hplc always miscellaneous 0.32%, maximum single miscellaneous 0.05%.
Dsc test result is consistent with embodiment 1 data.Spread out diffracting spectrum and embodiment 1 of x-ray powder keeps one substantially
Cause.
Embodiment 5: the preparation of Bisoprolol Fumarate i crystal formation
250g Bisoprolol Fumarate is dissolved in 500ml isopropanol, solution temperature is 60 DEG C；Negative pressure leaching；Filtrate
Under the stirring of 130r/min rotating speed, slow cooling is to 10 DEG C～13 DEG C crystallize 4.5h；Negative pressure leaching；Gained filter cake is put into vacuum and is dried
In case, 40 DEG C of insulation is dried 4h, obtains white powdery solids 236.5g, and yield is 94.6%.
This white powdery solids content is the relevant material of 99.8%, hplc always miscellaneous 0.27%, maximum single miscellaneous 0.04%.
Dsc test result is consistent with embodiment 1 data.Spread out diffracting spectrum and embodiment 1 of x-ray powder keeps one substantially
Cause.
Prepared by comparative example: according to us4258062 disclosure, prepare Bisoprolol Fumarate crude product.
Test example 1: dissolubility investigates test
In order to investigate the difference in dissolubility of the embodiment of the present application sample and comparative example, the application is respectively 25
DEG C, under the conditions of 37 DEG C in the hydrochloric acid of ph=1.0 (0.1n) and the acetic acid-sodium acetate buffer solution of ph=4.5, measure balance molten
Xie Du (saturated solution), result is as shown in table 1 below:
Table 1 dissolubility test result
Dissolubility test result shows, compared with Bisoprolol Fumarate crude product, the application crystal formation shows excellent molten
Xie Xing.
Test example 2 chemical stability investigates test
By embodiment sample and comparative example be respectively put into uncovered in the culture dish of cleaning divide placement, investigate in high temperature
(60 DEG C), high humidity (25 DEG C, rh90% ± 5%), high light (1.2 × 106Lux ± 500lx) under the conditions of sample stability, respectively
In sampling in 5 days and 10 days, investigate character, the relevant material of hplc is always miscellaneous, content, result see table 2- table 4:
Experimental result under the conditions of 60 DEG C of table 2 high temperature
Table 3 illumination 1.2 × 106Experimental result under the conditions of lux
Experimental result under the conditions of table 25 DEG C of rh90% of 4 high humidity
Can be seen that in 60 DEG C of conditions of high temperature 10 days by table 2-4, the content of the application and comparative example, character
All no significant changes, but the embodiment of the present invention 1～5 preparation Bisoprolol Fumarate sample relevant amount of substance be 0.20～
0.40%, and the relevant amount of substance of comparative example has gone up as 0.83%, that is, about amount of substance apparently higher than the application.
In illumination (1.2 × 106Lux, under the conditions of) when 10 days, the character of the application and comparative example is all unchanged, this
The relevant amount of substance of the Bisoprolol Fumarate sample of bright embodiment 1～5 preparation is 0.55～0.78%, and comparative example
Content range is changed into 96.6% from 99.5%, and substantially, relevant amount of substance has turned into 5.81% hence it is evident that being higher than the application, no for change
Meet the product quality of drug registration requirement.
Under the conditions of high humidity rh92.5% when 10 days, the application sample property is unchanged, but Comparative formulation occurs luming
Phenomenon, the relevant amount of substance of the Bisoprolol Fumarate sample of the embodiment of the present invention 1～5 preparation is 0.24～0.40%, content
Scope does not change substantially for 99.5%～99.9%；And the relevant amount of substance of comparative example increases to 0.95%, content
It is changed into 97.5% from 99.5%, be significantly greater than the application about amount of substance and changes of contents degree.
Shown by high temperature, high humidity, illumination effect factorial experimentss, the application preparation Bisoprolol Fumarate relevant
, all significantly lower than comparative sample 1, content, character are all more stable, and that is, the application stability of crystal form data substantially relatively contrasts for amount of substance
Example sample is more excellent, and product quality is more preferable.
Test example 3 draws moist test
By embodiment 1～5 sample and comparative example be respectively put into uncovered in the weighing botle of cleaning divide placement, investigate and exist
25 DEG C ± 1 DEG C, under the conditions of rh80% ± 2%, place the moisture absorption Gain weight of 24 hours, result is as shown in table 5 below:
Table 5 draws moist test result
Above-mentioned draw moist experiment and show, in 24 hours, the embodiment of the present application 1～5 sample draws wet weightening all below 1.5%,
Character does not change, and slightly draws moist；And Comparative formulation is drawn wet weightening and has been more than 2%, belong to and there is hygroscopic category.
It is known that drawing moist too good general can propose requirements at the higher level to follow-up formulation and technology, condition of storage, if desired for employing
Humidity resistance and lucifuge packaging of good performance, and increase because raw material moisture absorption is likely to result in unknown impuritie in production process
Plus or production process in affect dissolution.Accordingly, with respect to comparative example, the embodiment of the present application sample adopts common process condition
And sealed storage, can effectively guarantee the steady quality in product storing process and formulation process, have compared with prior art bright
Aobvious progress.
By above-mentioned dissolubility, stability, draw moist experiment display, with prior art Bisoprolol Fumarate crude product phase
The i crystal formation of the application preparation shows excellent product quality to ratio, has significantly progressive compared with prior art.
For the ordinary skill in the art it is evident that in the situation without departing from the application spirit or scope
Under, can to the application embodiment of the present invention with and preparation method thereof multiple modification and transformation of carrying out, therefore, the protection of the application
Scope covers the various modification and transformation that the application is carried out, as long as described modification or change are in claim and it is equal to
In the range of embodiment is covered.
Claims (8)
1. a kind of Bisoprolol Fumarate i crystal formation is it is characterised in that carry out x-ray powder mensure, its figure using cu-ka ray
Compose and there is the angle of diffraction shown in following table, interplanar distance and relative intensity:
2. Bisoprolol Fumarate i crystal formation according to claim 1 is it is characterised in that it has substantially as shown in Figure 1
X-ray powder diffraction spectrum.
3. Bisoprolol Fumarate i crystal formation according to claim 1 is it is characterised in that the dsc collection of illustrative plates of this crystal formation exists
103.63 DEG C having characteristic absorption peak.
4. a kind of method of the Bisoprolol Fumarate i crystal formation prepared described in claim 1 is it is characterised in that preparation method bag
Include following steps:
(1) Bisoprolol Fumarate is dissolved in isopropanol, Bisoprolol Fumarate is 1g with the mass volume ratio of isopropanol:
(2ml～5ml), 40 DEG C～60 DEG C of solution temperature；
(2) sucking filtration is carried out to step (1) resulting solution；
(3) under the stirring of 108r/min～136r/min rotating speed, step (2) gained filtrate slow cooling is analysed to 10 DEG C～20 DEG C
Brilliant 3h～5h；
(4) step (3) gained solid is carried out sucking filtration；
(5) step (4) gained filter cake is vacuum dried at 40 DEG C～60 DEG C 4h～8h.
5. the preparation method of Bisoprolol Fumarate i crystal formation according to claim 4 is it is characterised in that rich in step (1)
Horse acid bisoprolol is 1g:(3ml～4ml with the mass volume ratio of isopropanol), solution temperature is 45 DEG C～55 DEG C.
6. the preparation method of Bisoprolol Fumarate i crystal formation according to claim 4 is it is characterised in that institute in step (3)
Stating speed of agitator is 120r/min～130r/min, and recrystallization temperature is 10 DEG C～15 DEG C, and the crystallize time is 4h～4.5h.
7. the preparation method of Bisoprolol Fumarate i crystal formation according to claim 4 is it is characterised in that do in step (5)
The dry time is 5h～6h, and described temperature conditionss are 45 DEG C～55 DEG C.
8. the preparation method of Bisoprolol Fumarate i crystal formation according to claim 4 is it is characterised in that preparation method bag
Include following steps:
(1) 20g Bisoprolol Fumarate is dissolved in 60ml isopropanol, solution temperature is 55 DEG C；
(2) negative pressure leaching is carried out to step (1) resulting solution；
(3) filtrate 120r/min rotating speed stirring under, slow cooling to 15 DEG C～20 DEG C crystallize 4h；
(4) step (3) gained solid is carried out negative pressure leaching；
(5) step (4) gained filter cake is put into 55 DEG C of insulation in vacuum drying oven and 5.5h is dried, obtain white powdery solids
18.72g, yield is 93.6%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1590366A (en) * | 2002-07-12 | 2005-03-09 | 北京四环医药科技股份有限公司 | Improved method of preparing bisolol and its salt |
| EP2649996A1 (en) * | 2012-04-11 | 2013-10-16 | Laboratorios Del. Dr. Esteve, S.A. | Crystalline forms of sartans like telmisartan with beta blockers |
| CN103664657A (en) * | 2013-11-25 | 2014-03-26 | 四川大学 | New preparation method for bisoprolol fumarate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1590366A (en) * | 2002-07-12 | 2005-03-09 | 北京四环医药科技股份有限公司 | Improved method of preparing bisolol and its salt |
| EP2649996A1 (en) * | 2012-04-11 | 2013-10-16 | Laboratorios Del. Dr. Esteve, S.A. | Crystalline forms of sartans like telmisartan with beta blockers |
| CN103664657A (en) * | 2013-11-25 | 2014-03-26 | 四川大学 | New preparation method for bisoprolol fumarate |
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